Periodic leg movements during sleep are associated with polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD

Study Objectives: To examine association between periodic leg movements (PLM) and 13 single nucleotide polymorphisms (SNPs) in 6 loci known to increase risk of restless legs syndrome (RLS). Setting: Stanford Center for Sleep Sciences and Medicine and Clinical Research Unit of University of Wisconsin Institute for Clinical and Translational Research. Patients: Adult participants (n = 1,090, mean age = 59.7 years) from the Wisconsin Sleep Cohort (2,394 observations, 2000-2012). Design and Interventions: A previously validated automatic detector was used to measure PLMI. Thirteen SNPs within BTBD9, TOX3/BC034767, MEIS1 (2 unlinked loci), MAP2K5/SKOR1, and PTPRD were tested. Analyses were performed using a linear model and by PLM category using a 15 PLM/h cutoff. Statistical significance for loci was Bonferroni corrected for 6 loci (P < 8.3 × 10^-3). RLS symptoms were categorized into four groups: likely, possible, no symptoms, and unknown based on a mailed survey response. Measurements and Results: Prevalence of PLMI ≥ 15 was 33%. Subjects with PLMs were older, more likely to be male, and had more frequent RLS symptoms, a shorter total sleep time, and higher wake after sleep onset. Strong associations were found at all loci except one. Highest associations for PLMI > 15/h were obtained using a multivariate model including age, sex, sleep disturbances, and the best SNPs for each loci, yielding the following odds ratios (OR) and P values: BTBD9 rs3923809(A) OR = 1.65, P = 1.5×10 ^-8; TOX3/BC034767 rs3104788(T) OR = 1.35, P = 9.0 × 10 ^-5; MEIS1 rs12469063(G) OR = 1.38, P = 2.0 × 10^-4; MAP2K5/SKOR1 rs6494696(G) OR = 1.24, P = 1.3×10^-2; and PTPRD(A) rs1975197 OR = 1.31, P = 6.3×10^-3. Linear regression models also revealed significant PLM effects for BTBD9, TOX3/BC034767, and MEIS1. Co-varying for RLS symptoms only modestly reduced the genetic associations. Conclusions: Single nucleotide polymorphisms demonstrated to increase risk of RLS are strongly linked to increased PLM as well, although some loci may have more effects on one versus the other phenotype.